1. Field of the Invention
This invention is directed to a di-steroidal prodrug of estradiol and pharmaceutically acceptable salts thereof. The invention also includes pharmaceutical dosage units of the di-steroidal prodrug and a method of forming the di-steroidal prodrug of estradiol.
2. Related Background Art
Unbound 17β-estradiol is the most active, naturally occurring human estrogen. However, due to poor absorption and extensive first-pass metabolism in the gastrointestinal tract and liver following oral absorption, it is not generally orally active. Several methods have been utilized to increase its oral activity. A micronized form (to provide an increased surface area of drug for absorption) of estradiol which has sufficient oral bioavailability to be active is available. Alternatively estradiol can be formulated as a conjugate, e.g., conjugated equine estrogens which are essentially estrogen metabolites purified from the urine of pregnant mares that contain sulphate and glucuronide derivatives (Martindale 32ed, 1999, Pharmaceutical Press). These conjugates are orally active as they are hydrolyzed by enzymes in the lower gastrointestinal tract allowing absorption of the active estrogen. Another alternative is the oral administration of estradiol esters. Such compounds are known in the art for oral administration of estrogen and include estradiol-3,17-diacetate, estradiol-17-acetate, estradiol-3,17-valerate, estradiol-3-valerate and estradiol-17-valerate. These esters rapidly hydrolyze to free estradiol following oral administration.
U.S. Pat. No. 3,916,002 to Taubert et al. describes a number of oligomeric esters of androgenic, estrogenic and progestogenic steroids having the formula: R—O—CO—(CH2)n—CO—O—R, wherein n is between 2 and 8, and each R is a monovalent steroid radical. The steroid radical is derived from steroids having a hydroxyl substituent at one of the carbon atoms numbered 3, 16 or 17. They can be produced by esterification of the two carboxyl radicals of a dicarboxylic acid with a steroid alcohol having a hydroxyl radical substituent at carbon atoms numbered 3, 16, or 17. However, Taubert et al. does not disclose a novel di-steroidal prodrug of estradiol that is linked at the 3′ C position of the estradiol moiety.
A novel prodrug of estradiol that may increase oral activity would be highly advantageous.